Thursday, April 25, 2013

Goal: keep your transplanted organ permanently

Unless you have an identical twin, needing an organ transplant comes with a serious problem even beyond the fact that you need a transplant. Assuming the surgery goes well, the minute the new organ is grafted into your body, your immune system will recognize it as foreign, akin to invading bacteria, and seek to destroy it.

Taking the kidney for an example, there was a time 25 years ago when half of kidney transplant recipients lost their transplant due to immune rejection. The field of transplant immunology has in recent years become very good at preventing this during the first year after transplant using drugs that turn down the immune response, but long-term rejection remains commonplace.

The immune systems of many organ recipients eventually destroy transplanted kidneys over ten to 15 years. Worse yet, patients live through those years with a suppressed immune system; making them vulnerable to viral infections, some of which cause cancer.

Research efforts to solve these thorny, remaining problems in transplant immunology continue, but the field is under duress thanks to cuts in federal research funding, says UAB's Rosyln Mannon, M.D., director of research at the UAB Comprehensive Transplant Institute and a kidney transplant specialist. She was among the organizers of a recent transplant immunology symposium held by the institute.

Dr. Mannon sat down with The Mix to talk about research frontiers in transplantation, including efforts to design drugs that precisely turn down the activity of immune cells involved in transplant rejection, while ignoring those that fight infection.

Show notes for the podcast:

1:05 As we develop in the womb, special proteins are built on the surfaces of all our cells that serve as tags that say "self," and thus keep our immune cells from attacking them. A transplanted organ obviously has different cell-surface, protein labels.

1:31 When surgeons put in a transplanted organ, the proteins labels on the organ surfaces are picked up and carried by immune cells to nearby lymph nodes, where they trigger the building of an army of cells designed specifically to attack the new organ. Several sets of immune cells are swept up into the effort to destroy the transplanted organ (also called a graft), including T cells and antibodies, two workhorse cells of the adaptive immune system.

1:47 Thus, the response to a transplanted organ that immunologists must deal with when preventing transplant rejection includes a mix of proteins, including antibodies that glom onto and remove foreign cells, and cells that swarm to the transplant site and release destructive chemicals (e.g. cytokines).

3:15 The field of transplant immunology has been "incredibly successful" at preventing acute transplant rejection in the first year after the transplant using a subtle, powerful mix of drugs that damp down the immune system to protect transplanted organs.

3:39 The average person who receives a kidney this year from a diseased patient can expect the graft to last ten years. If the organ came from a living donor, the transplant may continue to function for 15 years, and especially if the organ came from a well matched family member. Despite these advances, all patients see their transplants fail eventually. About half of them "fail" because the patient dies, some from heart disease. Others organs fail because the medicines taken to suppress immune systems leave patients vulnerable to infection.

4:20 Physicians typically take a biopsy of a failing kidney to see why it has failed after working well for so long. In some cases, the slides will reveal that the immune system finally overcame immunosuppressive drugs to recognize the transplant as foreign and attack it. Interestingly, sometimes it will be one part of the immune system that finally tracks down the organ (e.g. antibodies), and sometimes another (T cells). In still other cases, the biopsy may reveal that a longtime, undetected viral infection has destroyed the organ, or maybe it was fibrosis, the wear-and-tear scarring that comes with age.

5:15 The failure of organ transplants many years after implantation for these varied reasons is the central, remaining problem facing transplant immunologists and their patients.

5:43 The drugs used to suppress the immune system on the way to protecting a transplanted organ have evolved. In the old days, transplant recipients received steroids like prednisone (an anti-allergy drug) and drugs called anti-metabolites. In the mid-1980s, a set of drugs called calceneurin inhibitors arrived, including cyclosporin and then later Prograf. Most patients in those days got large doses of drugs like these, some of which themselves scar the kidneys. Other risks of such therapy included knocking the immune system thoroughly enough to encourage viral infections like the Epstein-Barr virus, cytomegalovirus and related cancers viruses. The latter make random genetic changes in the cells they infect, some of which accidentally cause the abnormal growth seen in cancer. Presentations at the recent symposium talked about ways of fine-tuning immunosuppressive treatments to minimize damage related to their use.

7:47 Newer FDA-approved treatments appear to have fewer side effects, but still have the same problem as older drugs: they knock down the immune system broadly instead just the cells attacking the new organ. All physicians can do is gradually reduce the dose of immune suppressing medications over time under the assumption that the immune system has come to see the transplant as self, but doing so may result in the late-stage rejections currently observed five and ten years down the line.

8:53 Frontiers in the field include research efforts to design therapies that influence only the subsets of immune cells most associated with transplant rejection. Certain kinds of immune cells "remember" they have encountered a foreign protein, for instance. Therapies may destroy most of those cells, but those that remain eventually become capable of re-launching the attack on the transplant. On the other hand, one subset of T cells, called Tregs, are known to damp down the immune response in a careful way. What if engineers were able to deploy a person's own Tregs to damp down response to specific proteins on the surfaces of transplanted tissue?

10:11 Research efforts looking suppressing specific immune mechanisms, while the future of the field, are still in the early phases. Dr. Mannon hopes they suppress more surgically than the global suppression seen with older drugs.

10:45 The recent UAB transplant immunology symposium was timely, said Dr. Mannon, because UAB has been working to establish a collaborative consortium of transplant centers in the Southeast. UAB is one of the largest clinical transplant centers in the country, as is its partner in this symposium, the Emory Transplant Institute. Vanderbilt and the Medical College of South Carolina also have a strong interests in this area. The symposium was the first forum to identify and discuss the central, remaining problems in transplant immunology, and to launch joint efforts to solve them.

11:15 Among the research frontiers discussed was how best to arm patients with the ability to fight off infections without jeopardizing their transplants. One way may be to harness the bacteria that live in the human gut. What role do the bacteria that permanently colonize the body have in the immune system and transplant rejection? Can the interaction between our gut bugs and antibiotics for instance be manipulated to improve long-term outcomes of transplant patients by damping down system-wide inflammation?

14:24 Dr. Mannon is the newly elected president of the American Society of Transplantation, the second president in a row to come from UAB after Dr. Robert Gaston, M.D. UAB has for years been recognized across the Southeast for the large volume of clinical transplant procedures done here, but having the presidency sends a message to the nation about the strength of the basic and translational research underway.

15:45 The society has been very active on Capitol Hill in terms of lobbying for the support of related research, and that stance will continue during Dr. Mannon's term. As for the group's legislative agenda, they have been trying for 12 years to get a bill passed that would provide coverage for immunosuppressive therapy for the life of those with kidney transplants. Currently, Medicare pays for such medications for three years after the transplant, after which medications the become prohibitively expensive for those without private insurance. Another bill would ensure that those who donate a kidney to another person cannot have their coverage dropped by an insurer after they give the gift of life.